National Cancer Institute

at the National Institutes of Health

Non-Small Cell Lung Cancer Treatment (PDQ®)

Health Professional Version

Table of Contents

General Information About Non-Small Cell Lung Cancer (NSCLC)

NSCLC is any type of epithelial lung cancer other than small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can occur in unusual histologic variants. Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who have never smoked. As a class, NSCLCs are relatively insensitive to chemotherapy and radiation therapy compared with SCLC. Patients with resectable disease may be cured by surgery or surgery followed by chemotherapy. Local control can be achieved with radiation therapy in a large number of patients with unresectable disease, but cure is seen only in a small number of patients. Patients with locally advanced unresectable disease may achieve long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy, targeted agents, and other supportive measures.

Incidence and Mortality

Estimated new cases and deaths from lung cancer (NSCLC and SCLC combined) in the United States in 2014:[1]

New cases: 224,210.

Deaths: 159,260.

Lung cancer is the leading cause of cancer-related mortality in the United States.[1] The 5-year relative survival rate from 1995 to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate varies markedly depending on the stage at diagnosis, from 49% to 16% to 2% for patients with local, regional, and distant stage disease, respectively.[2]

Anatomy

NSCLC arises from the epithelial cells of the lung of the central bronchi to terminal alveoli. The histological type of NSCLC correlates with site of origin, reflecting the variation in respiratory tract epithelium of the bronchi to alveoli. Squamous cell carcinoma usually starts near a central bronchus. Adenocarcinoma and bronchioloalveolar carcinoma usually originate in peripheral lung tissue.

Anatomy of the respiratory system.

Pathogenesis

Smoking-related lung carcinogenesis is a multistep process. Squamous cell carcinoma and adenocarcinoma have defined premalignant precursor lesions. Before becoming invasive, lung epithelium may undergo morphological changes that include the following:

Hyperplasia.

Metaplasia.

Dysplasia.

Carcinoma in situ.

Dysplasia and carcinoma in situ are considered the principal premalignant lesions because they are more likely to progress to invasive cancer and less likely to spontaneously regress.

In addition, after resection of a lung cancer, there is a 1% to 2% risk per patient per year that a second lung cancer will occur.[3]

Pathology

NSCLC is a heterogeneous aggregate of histologies. The most common histologies include the following:

Epidermoid or squamous cell carcinoma.

Adenocarcinoma.

Large cell carcinoma.

These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar.

Risk Factors

Several risk factors contribute to the development of lung cancer. These risk factors may include the following:

The single most important risk factor for the development of lung cancer is smoking. For smokers, the risk for lung cancer is on average tenfold higher than in lifetime nonsmokers (defined as a person who has smoked <100 cigarettes in his or her lifetime). The risk increases with the quantity of cigarettes, duration of smoking, and starting age.

Smoking cessation results in a decrease in precancerous lesions and a reduction in the risk of developing lung cancer. Former smokers continue to have an elevated risk for lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on the lung cancer risk.[4]

Prevention

A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 patients with stage T1, N0 resected tumors, the rate was 1.8% per year for nonpulmonary second cancers and 1.6% per year for new lung cancers.[5] Other studies have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers.[6]

Because of the persistent risk of developing second lung cancers in former smokers, various chemoprevention strategies have been evaluated in randomized control trials. None of the phase III trials with the agents beta carotene, retinol, 13-cis-retinoic acid, [alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results.[7-11][Level of evidence: 1iiA] Chemoprevention of second primary cancers of the upper aerodigestive tract is undergoing clinical evaluation in patients with early-stage lung cancer.

Screening

In patients considered at high risk for developing lung cancer, the only screening modality for early detection that has been shown to alter mortality is low-dose helical CT scanning.[12] Studies of lung cancer screening with chest radiography and sputum cytology have failed to demonstrate that screening lowers lung cancer mortality rates.

Clinical Features

Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough or chest pain. Other presenting symptoms include the following:

Hemoptysis.

Malaise.

Weight loss.

Dyspnea.

Hoarseness.

Symptoms may result from local invasion or compression of adjacent thoracic structures such as compression involving the esophagus causing dysphagia, compression involving the laryngeal nerves causing hoarseness, or compression involving the superior vena cava causing facial edema and distension of the superficial veins of the head and neck. Symptoms from distant metastases may also be present and include neurological defect or personality change from brain metastases or pain from bone metastases. Infrequently, patients may present with symptoms and signs of paraneoplastic diseases such as hypertrophic osteoarthropathy with digital clubbing or hypercalcemia from parathyroid hormone-related protein. Physical examination may identify enlarged supraclavicular lymphadenopathy, pleural effusion or lobar collapse, unresolved pneumonia, or signs of associated disease such as chronic obstructive pulmonary disease or pulmonary fibrosis.

Diagnosis

Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient. Investigations of patients with suspected NSCLC focus on confirming the diagnosis and determining the extent of the disease.

The procedures used to determine the presence of cancer include the following:

History.

Physical examination.

Routine laboratory evaluations.

Chest x-ray.

Chest CT scan with infusion of contrast material.

Biopsy.

Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC.[13] Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

(Refer to the Staging Evaluation section of this summary for more information on tests and procedures used for staging.)

Molecular Features

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.[14] In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors.

Other genetic abnormalities of potential relevance to treatment decisions include translocations involving the anaplastic lymphoma kinase (ALK)-tyrosine kinase receptor, which are sensitive to ALK inhibitors, and amplification of MET (mesenchymal epithelial transition factor), which encodes the hepatocyte growth factor receptor. MET amplification has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

Prognostic Factors

Multiple studies have attempted to identify the prognostic importance of a variety of clinicopathologic factors.[6,15-18] Factors that have correlated with adverse prognosis include the following:

For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of more than 10%. These patients have been excluded from clinical trials evaluating aggressive multimodality interventions.

In multiple retrospective analyses of clinical trial data, advanced age alone has not been shown to influence response or survival with therapy.[33]

Refer to the separate treatment sections for each stage of NSCLC in this summary for more information about prognosis.

Because treatment is not satisfactory for almost all patients with NSCLC, eligible patients should be considered for clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Related Summaries

Other PDQ summaries containing information related to lung cancer include the following:

van Zandwijk N, Dalesio O, Pastorino U, et al.: EUROSCAN, a randomized trial of vitamin A and N-acetylcysteine in patients with head and neck cancer or lung cancer. For the EUropean Organization for Research and Treatment of Cancer Head and Neck and Lung Cancer Cooperative Groups. J Natl Cancer Inst 92 (12): 977-86, 2000. [PUBMED Abstract]

Cellular Classification of NSCLC

Malignant non-small cell epithelial tumors of the lung are classified by the World Health Organization (WHO)/International Association for the Study of Lung Cancer (IASLC). There are three main subtypes of non-small cell lung cancer (NSCLC), including the following:

Squamous cell carcinoma

Most squamous cell carcinomas of the lung are located centrally, in the larger bronchi of the lung. Squamous cell carcinomas are linked more strongly with smoking than other forms of NSCLC. The incidence of squamous cell carcinoma of the lung has been decreasing in recent years.

Adenocarcinoma

Adenocarcinoma is now the most common histologic subtype in many countries, and subclassification of adenocarcinoma is important. One of the biggest problems with lung adenocarcinomas is the frequent histologic heterogeneity. In fact, mixtures of adenocarcinoma histologic subtypes are more common than tumors consisting purely of a single pattern of acinar, papillary, bronchioloalveolar, and solid adenocarcinoma with mucin formation.

Criteria for the diagnosis of bronchioloalveolar carcinoma have varied widely in the past. The current WHO/IASLC definition is much more restrictive than that previously used by many pathologists because it is limited to only noninvasive tumors.

If stromal, vascular, or pleural invasion are identified in an adenocarcinoma that has an extensive bronchioloalveolar carcinoma component, the classification would be an adenocarcinoma of mixed subtype with predominant bronchioloalveolar pattern and a focal acinar, solid, or papillary pattern, depending on which pattern is seen in the invasive component. However, the future of bronchioloalveolar carcinoma as a distinct clinical entity is unclear; a multidisciplinary expert panel representing the IASLC, the American Thoracic Society, and the European Respiratory Society proposed a major revision of the classification of adenocarcinomas in 2011 that entails a reclassification of what was called bronchioloalveolar carcinoma into newly defined histologic subgroups.

The following variants of adenocarcinoma are recognized in the WHO/IASLC classification:

Well-differentiated fetal adenocarcinoma.

Mucinous (colloid) adenocarcinoma.

Mucinous cystadenocarcinoma.

Signet ring adenocarcinoma.

Clear cell adenocarcinoma.

Large cell carcinoma

In addition to the general category of large cell carcinoma, several uncommon variants are recognized in the WHO/IASLC classification, including the following:

LCNEC.

Basaloid carcinoma.

Lymphoepithelioma-like carcinoma.

Clear cell carcinoma.

Large cell carcinoma with rhabdoid phenotype.

Basaloid carcinoma is also recognized as a variant of squamous cell carcinoma, and rarely, adenocarcinomas may have a basaloid pattern; however, in tumors without either of these features, they are regarded as a variant of large cell carcinoma.

Neuroendocrine tumors

LCNEC is recognized as a histologically high-grade non-small cell carcinoma. It has a very poor prognosis similar to that of small cell lung cancer (SCLC). Atypical carcinoid is recognized as an intermediate-grade neuroendocrine tumor with a prognosis that falls between typical carcinoid and high-grade SCLC and LCNEC.

Neuroendocrine differentiation can be demonstrated by immunohistochemistry or electron microscopy in 10% to 20% of common NSCLCs that do not have any neuroendocrine morphology. These tumors are not formally recognized within the WHO/IASLC classification scheme because the clinical and therapeutic significance of neuroendocrine differentiation in NSCLC is not firmly established. These tumors are referred to collectively as NSCLC with neuroendocrine differentiation.

Carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements

This is a group of rare tumors. Spindle cell carcinomas and giant cell carcinomas comprise only 0.4% of all lung malignancies, and carcinosarcomas comprise only 0.1% of all lung malignancies. In addition, this group of tumors reflects a continuum in histologic heterogeneity as well as epithelial and mesenchymal differentiation. On the basis of clinical and molecular data, biphasic pulmonary blastoma is regarded as part of the spectrum of carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements.

Molecular Features

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.[2] In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. Other mutations of potential relevance to treatment decisions include:

Kirsten rat sarcoma viral oncogene (KRAS).

Anaplastic lymphoma kinase receptor (ALK).

Human epidermal growth factor receptor 2 (HER2).

V-raf murine sarcoma viral oncogene homolog B1 (BRAF).

PIK3 catalytic protein alpha (PI3KCA).

AKT1.

MAPK kinase 1 (MAP2K1 or MEK1).

MET, which encodes the hepatocyte growth factor receptor (HGFR).

These mutations are mutually exclusive, except for those in PIK3CA and EGFR mutations and ALK translocations.[3]

EGFR and ALK mutations predominate in adenocarcinomas that develop in nonsmokers, and KRAS and BRAF mutations are more common in smokers or former smokers. EGFR mutations strongly predict the improved response rate and progression-free survival of EGFR inhibitors. In a set of 2,142 lung adenocarcinoma specimens from patients treated at Memorial Sloan Kettering Cancer Center, EGFR exon 19 deletions and L858R were found in 15% of tumors from former smokers (181 of 1,218; 95% CI, 13–17), 6% from current smokers (20 of 344; 95% CI, 4–9), and 52% from never-smokers (302 of 580; 95% CI, 48–56; P < .001 for ever- vs. never-smokers).[4]

Fusions of ALK with EML4 genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. Other mutations that occur in less than 5% of NSCLC tumors include:

HER2, present in 2% of tumors.

PI3KCA, present in 2% of tumors.

AKT1, present in 1% of tumors.

BRAF mutations, present in 1% to 3% of tumors.

BRAF mutations are mutually exclusive of EGFR and KRAS mutations. Somatic mutations in MAP2K1 (also known as MEK) have been identified in 1% of NSCLC. MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

Stage Information for NSCLC

Background

In NSCLC, the determination of stage is important in terms of therapeutic and prognostic implications. Careful initial diagnostic evaluation to define the location and to determine the extent of primary and metastatic tumor involvement is critical for the appropriate care of patients.

In general, symptoms, physical signs, laboratory findings, or perceived risk of distant metastasis lead to an evaluation for distant metastatic disease. Additional tests such as bone scans and computed tomography (CT)/magnetic resonance imaging (MRI) of the brain may be performed if initial assessments suggest metastases or if patients with stage III disease are under consideration for aggressive local and combined modality treatments.

Stage has a critical role in the selection of therapy. The stage of disease is based on a combination of clinical factors and pathological factors.[1] The distinction between clinical stage and pathological stage should be considered when evaluating reports of survival outcome.

Procedures used to determine staging include the following:

History.

Physical examination.

Routine laboratory evaluations.

Chest x-ray.

Chest CT scan with infusion of contrast material.

Fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning.

Procedures used to obtain tissue samples include bronchoscopy, mediastinoscopy, or anterior mediastinotomy. Pathological staging of NSCLC requires the following:

Examination of the tumor.

Resection margins.

Lymph nodes.

Prognostic and treatment decisions are based on some of the following factors:

Knowledge of histologic type.

Tumor size and location.

Involvement of pleura.

Surgical margins.

Status and location of lymph nodes by station.

Tumor grade.

Lymphovascular invasion.

At diagnosis, patients with NSCLC can be divided into the following three groups that reflect both the extent of the disease and the treatment approach:

The association between survival and the number of examined lymph nodes during surgery for patients with stage I NSCLC treated with definitive surgical resection was assessed from the population-based Surveillance, Epidemiology and End Results database for the period from 1990 to 2000.[3] A total of 16,800 patients were included in the study.

The overall survival (OS) analysis for patients without radiation therapy demonstrated that in comparison to the reference group (one to four lymph nodes), patients with five to eight lymph nodes examined during surgery had a modest but statistically significant increase in survival, with a proportionate hazard ratio (HR) of 0.90 (95% confidence interval [CI], 0.84–0.97). For patients with 9 to 12 lymph nodes and 13 to 16 lymph nodes examined, HRs were 0.86 (95% CI, 0.79–0.95) and 0.78 (95% CI, 0.68–0.90), respectively. There appeared to be no incremental improvement after evaluating more than 16 lymph nodes. The corresponding results for lung cancer–specific mortality and for patients receiving radiation therapy were not substantially different.

These results indicate that patient survival following resection for NSCLC is associated with the number of lymph nodes evaluated during surgery. Because this is most likely the result of a reduction-of-staging error, namely, a decreased likelihood of missing positive lymph nodes with an increasing number of lymph nodes sampled, it suggests that an evaluation of nodal status should include 11 to 16 lymph nodes.

CT imaging

CT scanning is primarily used for determining the size of the tumor. The CT scan should extend inferiorly to include the liver and adrenal glands. MRI scans of the thorax and upper abdomen do not appear to yield advantages over CT scans.[4]

Evidence (CT scan):

A systematic review of the medical literature relating to the accuracy of CT scanning for noninvasive staging of the mediastinum in patients with lung cancer has been conducted. In the 35 studies published between 1991 and June 2006, 5,111 evaluable patients were identified. Almost all studies specified that CT scanning was performed following the administration of IV contrast material and that a positive test result was defined as the presence of one or more lymph nodes that measured larger than 1 cm on the short-axis diameter.[5]

The median prevalence of mediastinal metastasis was 28% (range, 18%–56%).

The results from the systematic review are similar to those of a large meta-analysis that reported the median sensitivity and specificity of CT scanning for identifying malignant mediastinal nodes as 61% and 79%, respectively.[6]

An earlier meta-analysis reported average sensitivity and specificity of 64% and 74%, respectively.[7]

FDG-PET scanning

The wider availability and use of FDG-PET scanning for staging has modified the approach to staging mediastinal lymph nodes and distant metastases.

Randomized trials evaluating the utility of FDG-PET scanning in potentially resectable NSCLC report conflicting results in terms of the relative reduction in the number of noncurative thoracotomies.

Although the current evidence is conflicting, FDG-PET scanning may improve results of early-stage lung cancer by identifying patients who have evidence of metastatic disease that is beyond the scope of surgical resection and that is not evident by standard preoperative staging procedures.

Evidence (FDG-PET scan):

A systematic review, an expansion of a health technology assessment conducted in 2001 by the Institute for Clinical and Evaluative Sciences, evaluated the accuracy and utility of FDG-PET scanning in the diagnosis and staging of lung cancer.[8] Through a systematic search of the literature, 12 evidence summary reports and 15 prospective studies of the diagnostic accuracy of FDG-PET scanning were identified. FDG-PET scanning appears to be superior to CT imaging for mediastinal staging in NSCLC. FDG-PET scanning also appears to have high sensitivity and reasonable specificity for differentiating benign from malignant lesions as small as 1 cm.

A systematic review of the medical literature relating to the accuracy of FDG-PET scanning for noninvasive staging of the mediastinum in patients with lung cancer identified 44 studies published between 1994 and 2006 with 2,865 evaluable patients.[5] The median prevalence of mediastinal metastases was 29% (range, 5%–64%). Pooled estimates of sensitivity and specificity for identifying mediastinal metastasis were 74% (95% CI, 69%–79%) and 85% (95% CI, 82%–88%), respectively. Corresponding positive and negative likelihood ratios for mediastinal staging with FDG-PET scanning were 4.9 and 0.3, respectively. These findings demonstrate that FDG-PET scanning is more accurate than CT scanning for staging of the mediastinum in patients with lung cancer.

Cost effectiveness of FDG-PET scanning

Decision analyses demonstrate that FDG-PET scanning may reduce the overall costs of medical care by identifying patients with falsely negative CT scans in the mediastinum or otherwise undetected sites of metastases.[9-11] Studies concluded that the money saved by forgoing mediastinoscopy in FDG-PET-positive mediastinal lesions was not justified because of the unacceptably high number of false-positive results.[9-11] A randomized study found that the addition of FDG-PET scanning to conventional staging was associated with significantly fewer thoracotomies.[12] A second randomized trial evaluating the impact of FDG-PET scanning on clinical management found that FDG-PET scanning provided additional information regarding appropriate stage but did not lead to significantly fewer thoracotomies.[13]

Combination of CT imaging and FDG-PET scanning

The combination of CT imaging and FDG-PET scanning has greater sensitivity and specificity than CT imaging alone.[14]

Evidence (CT/FDG-PET scan):

If there is no evidence of distant metastatic disease on CT scan, FDG-PET scanning complements CT scan staging of the mediastinum. Numerous nonrandomized studies of FDG-PET scanning have evaluated mediastinal lymph nodes using surgery (i.e., mediastinoscopy and/or thoracotomy with mediastinal lymph node dissection) as the gold standard of comparison.

In a meta-analysis evaluating the conditional test performance of FDG-PET scanning and CT scanning, the median sensitivity and specificity of FDG-PET scans were reported as 100% and 78%, respectively, in patients with enlarged lymph nodes.[6] FDG-PET scanning is considered very accurate in identifying malignant nodal involvement when nodes are enlarged. However, FDG-PET scanning will falsely identify a malignancy in approximately one-fourth of patients with nodes that are enlarged for other reasons, usually as a result of inflammation or infection.[15,16]

The median sensitivity and specificity of FDG-PET scanning in patients with normal-sized mediastinal lymph nodes were 82% and 93%, respectively.[6] These data indicate that nearly 20% of patients with normal-sized nodes but with malignant involvement had falsely negative FDG-PET scan findings.

For patients with clinically operable NSCLC, the recommendation is for a biopsy of mediastinal lymph nodes that were found to be larger than 1 cm in shortest transverse axis on chest CT scan or were found to be positive on FDG-PET scan. Negative FDG-PET scanning does not preclude biopsy of radiographically enlarged mediastinal lymph nodes. Mediastinoscopy is necessary for the detection of cancer in mediastinal lymph nodes when the results of the CT scan and FDG-PET scan do not corroborate each other.

Evaluation of brain metastasis

Patients at risk for brain metastases may be staged with CT or MRI scans. One study randomly assigned 332 patients with potentially operable NSCLC and no neurological symptoms to brain CT or MRI imaging to detect occult brain metastasis before lung surgery. MRI showed a trend towards a higher preoperative detection rate than CT scan (P = .069), with an overall detection rate of approximately 7% from pretreatment to 12 months after surgery.[17] Patients with stage I or stage II disease had a detection rate of 4% (i.e., eight detections out of 200 patients); however, individuals with stage III disease had a detection rate of 11.4% (i.e., 15 detections out of 132 patients). The mean maximal diameter of the brain metastases was significantly smaller in the MRI group. Whether the improved detection rate of MRI translates into improved outcome remains unknown. Not all patients are able to tolerate MRI, and for these patients contrast-enhanced CT scan is a reasonable substitute.

Evaluation of distant metastasis other than the brain

Numerous nonrandomized, prospective, and retrospective studies have demonstrated that FDG-PET scanning seems to offer diagnostic advantages over conventional imaging in staging distant metastatic disease; however, standard FDG-PET scans have limitations. FDG-PET scans may not extend below the pelvis and may not detect bone metastases in the long bones of the lower extremities. Because the metabolic tracer used in FDG-PET scanning accumulates in the brain and urinary tract, FDG-PET scanning is not reliable for detection of metastases in these sites.[17]

The Revised International System for Staging Lung Cancer

The Revised International System for Staging Lung Cancer, based on information from a clinical database of more than 5,000 patients, was adopted in 2010 by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer.[18,19] These revisions provide greater prognostic specificity for patient groups; however, the correlation between stage and prognosis predates the widespread availability of PET imaging.

Summary of Changes

This staging system is now recommended for the classification of both NSCLC and small cell lung carcinomas and for carcinoid tumors of the lung.[19]

The T (primary tumor) classifications have been redefined as follows:[19]

T1 has been subclassified into T1a (≤2 cm in size) and T1b (>2–3 cm in size).

T2 has been subclassified into T2a (>3–5 cm in size) and T2b (>5–7 cm in size).

T2 (>7 cm in size) has been reclassified as T3.

Multiple tumor nodules in the same lobe have been reclassified from T4 to T3.

Multiple tumor nodules in the same lung but a different lobe have been reclassified from M1 to T4.

No changes have been made to the N (regional lymph nodes) classification. However, a new international lymph node map defining the anatomical boundaries for lymph node stations has been developed.

The M (distant metastasis) classifications have been redefined as follows:

M1 has been subdivided into M1a and M1b.

Malignant pleural and pericardial effusions have been reclassified from T4 to M1a.

bThe uncommon superficial spreading of the tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.

IA

T1a, N0, M0

T1a = Tumor ≤2 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).b

N0 = No regional lymph node metastasis.

M0 = No distant metastasis.

T1b, N0, M0

T1b = Tumor >2 cm but ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).b

bThe uncommon superficial spreading of the tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.

IB

T2a, N0, M0

T2a = Tumor >3 cm but ≤5 cm in greatest dimension, or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2); or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

bThe uncommon superficial spreading of the tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.

IIA

T2b, N0, M0

T2b = Tumor >5 cm but ≤7 cm or less in greatest dimension, or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2); or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

N0 = No regional lymph node metastasis.

M0 = No distant metastasis.

T1a, N1, M0

T1a = Tumor ≤2 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).b

T1b = Tumor >2 cm but ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).b

T2a = Tumor >3 cm but ≤5 cm in greatest dimension, or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2); or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

bThe uncommon superficial spreading of the tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.

IIB

T2b, N1, M0

T2b = Tumor >5 cm but ≤7 cm in greatest dimension, or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2); or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

T3 = Tumor >7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium or tumor in the main bronchus (<2 cm distal to the carinab but without involvement of the carina) or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe.b

T1b = Tumor >2 cm but ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).b

T2a = Tumor >3 cm but ≤5 cm in greatest dimension, or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2); or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

T2b = Tumor >5 cm but ≤7 cm in greatest dimension, or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2); or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

T3 = Tumor >7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium or tumor in the main bronchus (<2 cm distal to the carinab but without involvement of the carina) or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe.

T3 = Tumor >7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium or tumor in the main bronchus (<2 cm distal to the carinab but without involvement of the carina) or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe.

T4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe.

N0 = No regional lymph node metastasis.

M0 = No distant metastasis.

T4, N1, M0

T4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe.

T1b = Tumor >2 cm but ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).b

T2a = Tumor >3 cm but ≤5 cm or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2); or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

T2b = Tumor >5 cm but ≤7 cm or tumor with any of the following features: involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2); or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

T3 = Tumor >7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium or tumor in the main bronchus (<2 cm distal to the carinab but without involvement of the carina) or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe.

T4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe.

T4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe.

bThe uncommon superficial spreading of the tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.

cMost pleural (and pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element, and the patient should be classified as M0.

IV

Any T, Any N, M1a OR Any T, Any N, M1b

TX = Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy.

T0 = No evidence of primary tumor.

Tis = Carcinoma in situ.

T1 = Tumor ≤3 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus).b

T2 = Tumor >3 cm but ≤7 cm in greatest dimension, or tumor with any of the following features (T2 tumors with these features are classified T2a if ≤5 cm): involves main bronchus, ≥2 cm distal to the carina; invades visceral pleura (PL1 or PL2); or is associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung.

T3 = Tumor >7 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium or tumor in the main bronchus (<2 cm distal to the carinab but without involvement of the carina) or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe.

T4 = Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, or separate tumor nodule(s) in a different ipsilateral lobe.

Treatment Option Overview for NSCLC

In NSCLC, results of standard treatment are poor except for the most localized cancers. All newly diagnosed patients with NSCLC are potential candidates for studies evaluating new forms of treatment.

Surgery is the most potentially curative therapeutic option for this disease. Postoperative chemotherapy may provide an additional benefit to patients with resected NSCLC. Radiation therapy combined with chemotherapy can produce a cure in a small number of patients and can provide palliation in most patients. Prophylactic cranial irradiation (PCI) may reduce the incidence of brain metastases, but there is no evidence of a survival benefit and the effect of PCI on quality of life is not known.[1,2] In patients with advanced-stage disease, chemotherapy or epidermal growth factor receptor (EGFR) kinase inhibitors offer modest improvements in median survival, though overall survival is poor.[3,4]

Chemotherapy has produced short-term improvement in disease-related symptoms in patients with advanced NSCLC. Several clinical trials have attempted to assess the impact of chemotherapy on tumor-related symptoms and quality of life. In total, these studies suggest that tumor-related symptoms may be controlled by chemotherapy without adversely affecting overall quality of life;[5,6] however, the impact of chemotherapy on quality of life requires more study. In general, medically fit elderly patients with good performance status obtain the same benefits from treatment as younger patients.

The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease.[7] In particular, genetic abnormalities in EGFR, MAPK, PI3K signaling pathways in subsets of NSCLC may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. EGFR mutations strongly predict the improved response rate and progression-free survival of inhibitors of EGFR. Fusions of ALK with EML4 genes form translocation products that occur in ranges from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.

The standard treatment options for each stage of NSCLC are presented in Table 11.

Follow-Up

Several small series have reported that reduction in fluorodeoxyglucose-positron emission tomography (FDG-PET) after chemotherapy, radiation therapy, or chemoradiation therapy correlates with pathological complete response and favorable prognosis.[8-15] Studies have used different timing of assessments, FDG-PET parameters, and cutpoints to define FDG-PET response. Reduction in maximum standardized uptake value (SUV) of more than 80% predicted for complete pathological response with a sensitivity of 90%, specificity of 100%, and accuracy of 96%.[16] Median survival after resection was greater for patients with tumor SUV values of less than 4 (56 mo vs. 19 mo).[15] Patients with complete metabolic response following radiation therapy were reported to have median survivals of 31 months versus 11 months.[17]

FDG-PET may be more sensitive and specific than computed tomography scan in assessing response to induction therapy. Optimal timing imaging remains to be defined; however, one study suggests that greater sensitivity and specificity of FDG-PET is achieved if repeat imaging is delayed until 30 days after radiation therapy.[16]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Occult NSCLC Treatment

In occult lung cancer, a diagnostic evaluation often includes chest x-ray and selective bronchoscopy with close follow-up (e.g., computed tomography scan), when needed, to define the site and nature of the primary tumor; tumors discovered in this fashion are generally early stage and curable by surgery.

After discovery of the primary tumor, treatment involves establishing the stage of the tumor. Therapy is identical to that recommended for other NSCLC patients with similar stage disease.

Standard Treatment Options for Occult NSCLC

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with occult non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Standard Treatment Options for Stage 0 NSCLC

Surgery

Segmentectomy or wedge resection are used to preserve maximum normal pulmonary tissue since patients with stage 0 NSCLC are at a high risk for second lung cancers. Because these tumors are by definition noninvasive and incapable of metastasizing, they should be curable with surgical resection; however, such lesions, when identified, are often centrally located and may require a lobectomy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stages IA and IB NSCLC Treatment

Standard Treatment Options for Stages IA and IB NSCLC

Chemotherapy and radiation therapy have not been shown to improve outcomes in stage I NSCLC that has been completely resected.

Surgery

Surgery is the treatment of choice for patients with stage I NSCLC. A lobectomy or segmental, wedge, or sleeve resection may be performed as appropriate. Patients with impaired pulmonary function are candidates for segmental or wedge resection of the primary tumor. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. The immediate postoperative mortality rate is age related, but a 3% to 5% mortality rate with lobectomy can be expected.[1]

Evidence (surgery):

The Lung Cancer Study Group conducted a randomized study (LCSG-821) that compared lobectomy with limited resection for patients with stage I lung cancer. Results of the study showed the following:[2]

A reduction in local recurrence for patients treated with lobectomy compared with those treated with limited excision.

No significant difference in overall survival (OS).

Similar results have been reported from a nonrandomized comparison of anatomic segmentectomy and lobectomy.[3]

A survival advantage was noted with lobectomy for patients with tumors larger than 3 cm but not for those with tumors smaller than 3 cm.

The rate of locoregional recurrence was significantly less after lobectomy, regardless of primary tumor size.

Those treated with wedge or segmental resections had a local recurrence rate of 50% (i.e., 31 recurrences out of 62 patients) despite having undergone complete resections.[4]

The Cochrane Collaboration group reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.[5] A pooled analysis of three trials reported the following:

There was a significant reduction in any cancer recurrence (local or distant) in the CMLND group (relative risk [RR], 0.79; 95% CI, 0.66–0.95; P = .01) that appeared mainly because of a reduction in the number of distant recurrences (RR, 0.78; 95% CI, 0.61–1.00; P = .05).

There was no difference in operative mortality.

Air leak lasting more than 5 days was significantly more common in patients assigned to CMLND (RR, 2.94; 95% CI, 1.01–8.54; P = .05).

Current evidence suggests that lung cancer resection combined with CMLND is associated with a small-to-modest improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal nodes in patients with stage I, II, or IIIA NSCLC.[5][Level of evidence: 1iiA]

Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[6]

Limitations of evidence (surgery):

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and the potential methodological weaknesses of the trials.

Adjuvant therapy

Many patients treated surgically subsequently develop regional or distant metastases.[7] Such patients are candidates for entry into clinical trials evaluating postoperative treatment with chemotherapy or radiation therapy following surgery. At present, neither chemotherapy nor radiation therapy has been found to improve the outcome of patients with stage I NSCLC that has been completely resected.

Adjuvant radiation therapy

The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated and has not been found to improve the outcome of patients with completely resected stage I NSCLC.[8]

Evidence (adjuvant radiation therapy):

A meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported the following:[8]

An 18% relative increase in the risk of death for patients who received PORT compared with surgery alone (HR, 1.18; P = .002). This is equivalent to an absolute detriment of 6% at 2 years (95% CI, 2–9), reducing OS from 58% to 52%. Exploratory subgroup analyses suggested that this detrimental effect was most pronounced for patients with stage I/II, N0-N1 disease, whereas for patients with stage III, N2 disease, there was no clear evidence of an adverse effect.

Further analysis is needed to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.

Adjuvant chemotherapy

Based on a meta-analysis, postoperative chemotherapy is not recommended outside of a clinical trial for patients with completely resected stage I NSCLC.[9,10][Level of evidence: 1iiA]

Evidence (adjuvant chemotherapy for stage I NSCLC):

Data on individual patient outcomes were collected and pooled into a meta-analysis from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.[11]

With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy.

The apparent greater benefit seen with vinorelbine should be interpreted cautiously as vinorelbine and cisplatin combinations generally required that a higher dose of cisplatin be given. Chemotherapy effect was higher in patients with a better performance status.

There was no interaction between chemotherapy effect and any of the following:

Sex.

Age.

Histology.

Type of surgery.

Planned radiation therapy.

Planned total dose of cisplatin.

Several other randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stages I, II, and IIIA NSCLC.[11-17]

Although there is sufficient evidence that postoperative chemotherapy is effective in patients with stage II or stage IIIA NSCLC, its usefulness in patients with stage IB NSCLC is less clear.

Evidence (adjuvant chemotherapy for stage IB NSCLC):

The Cancer and Leukemia Group B study (CALGB-9633) addressed the results of adjuvant carboplatin and paclitaxel versus observation for OS in 344 patients with resected stage IB (i.e., pathological T2, N0) NSCLC. Within 4 to 8 weeks of resection, patients were randomly assigned to postoperative chemotherapy or observation.[18]

Survival was not significantly different (HR, 0.83; CI, 0.64–1.08; P = .12) at a median follow-up of 74 months.

Grades 3 to 4 neutropenia were the predominant toxicity; there were no treatment-related deaths.

Given the magnitude of observed survival differences, CALGB-9633 may have been underpowered to detect small but clinically meaningful improvements in survival. In addition, the use of a carboplatin versus a cisplatin combination might have affected the results. At present, there is no reliable evidence that postoperative chemotherapy improves survival of patients with stage IB NSCLC.[18] [Level of evidence: 1iiA]

Radiation therapy

Patients with potentially resectable tumors with medical contraindications to surgery or those with inoperable stage I disease and with sufficient pulmonary reserve may be candidates for radiation therapy with curative intent. Primary radiation therapy often consists of approximately 60 Gy delivered with megavoltage equipment to the midplane of the known tumor volume using conventional fractionation. A boost to the cone down field of the primary tumor is frequently used to enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures to the extent possible is needed for optimal results; this requires the use of a simulator.

Prognosis:

In the two largest retrospective radiation therapy series, patients with inoperable disease treated with definitive radiation therapy achieved 5-year survival rates of 10% and 27%.[19,20] Both series found that patients with T1, N0 tumors had better outcomes, and 5-year survival rates of 60% and 32% were found in this subgroup.

Evidence (radiation therapy):

A single report of patients older than 70 years who had resectable lesions smaller than 4 cm but who had medically inoperable disease or who refused surgery reported the following:[21]

Survival at 5 years after radiation therapy with curative intent was comparable with a historical control group of patients of similar age who were resected with curative intent.

The addition of endobronchial brachytherapy improved local disease control compared with external-beam radiation therapy.[4][Level of evidence: 3iiiDiii]

A substantial number of patients are ineligible for standard surgical resection because of comorbid conditions that are associated with unacceptably high perioperative risk. Observation and radiation therapy may be considered for these patients.[22-24] Nonrandomized observation studies comparing treatment outcomes associated with resection, radiation therapy, and observation have demonstrated shorter survival times and higher mortality for patients treated with observation only.[22] There are a number of approaches to delivery of radiation therapy, including conventional external-beam radiation therapy, stereotactic total-body radiation therapy, and others, and limited reliable data from comparative trials to determine which yield superior outcomes.[23,24]

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

Clinical trials of postoperative chemoprevention (as evidenced in the ECOG-5597 trial, for example).

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Standard Treatment Options for Stages IIA and IIB NSCLC

Adjuvant radiation therapy has not been show to improve outcomes in patients with stages II NSCLC.

Surgery

Surgery is the treatment of choice for patients with stage II NSCLC. A lobectomy, pneumonectomy, or segmental resection, wedge resection, or sleeve resection may be performed as appropriate. Careful preoperative assessment of the patient’s overall medical condition, especially the patient’s pulmonary reserve, is critical in considering the benefits of surgery. Despite the immediate and age-related postoperative mortality rate, a 5% to 8% mortality rate with pneumonectomy or a 3% to 5% mortality rate with lobectomy can be expected.

Evidence (surgery):

The Cochrane Collaboration group reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.[1] A pooled analysis of three trials reported the following:

There was a significant reduction in any cancer recurrence (local or distant) in the CMLND group (relative risk [RR], 0.79; 95% CI, 0.66–0.95; P = .01) that appeared mainly as the result of a reduction in the number of distant recurrences (RR, 0.78; 95% CI, 0.61–1.00; P = .05).

There was no difference in operative mortality.

Air leak lasting more than 5 days was significantly more common in patients assigned to CMLND (RR, 2.94; 95% CI, 1.01–8.54; P = .05).

Current evidence suggests that lung cancer resection combined with CMLND is associated with a small-to-modest improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal nodes in patients with stage I, II, or IIIA NSCLC.[1][Level of evidence: 1iiA]

Preliminary analyses of operative morbidity and mortality showed comparable rates from the procedures.[2]

Limitations of evidence (surgery):

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and potential methodological weaknesses of the trials.

Neoadjuvant chemotherapy

The role of chemotherapy prior to surgery was tested in clinical trials. The proposed benefits of preoperative chemotherapy include the following:

The Cochrane Collaboration Review group reported a systematic review and meta-analysis of seven randomized controlled trials that included 988 patients and evaluated the addition of preoperative chemotherapy to surgery versus surgery alone. These trials evaluated patients with stages I, II, and IIIA NSCLC.[3]

Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease, from 14% to 20% at 5 years (HR, 0.82; 95% CI, 0.69–0.97; P = .022).[3][Level of evidence: 1iiA]

This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.

In the largest trial reported to date, 519 patients were randomly assigned to receive either surgery alone or three cycles of platinum-based chemotherapy followed by surgery. Most patients (61%) had clinical stage I disease; 31% had stage II disease; and 7% had stage III disease.[4]

Postoperative complications were similar between groups, and no impairment of quality of life was observed.

There was no evidence of a benefit in terms of overall survival (OS) (HR, 1.02; 95% CI, 0.80–1.31; P = .86).

Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of neoadjuvant (preoperative) chemotherapy (1,507 patients; HR, 0.88; 95% CI, 0.76–1.01; P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.

Adjuvant radiation therapy

The value of postoperative (adjuvant) radiation therapy (PORT) has been evaluated.[5]

Evidence (adjuvant radiation therapy):

A meta-analysis, based on the results of ten randomized controlled trials and 2,232 individuals, reported the following:[5]

An 18% relative increase in the risk of death for patients who received PORT compared with surgery alone (HR, 1.18; P = .002). This is equivalent to an absolute detriment of 6% at 2 years (95% CI, 2%–9%), reducing OS from 58% to 52%. Exploratory subgroup analyses suggested that this detrimental effect was most pronounced for patients with stage I/II, N0–N1 disease, whereas for patients with stage III, N2 disease there was no clear evidence of an adverse effect.

Further analysis is needed to determine whether these outcomes can potentially be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.

Adjuvant chemotherapy

The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected stage II NSCLC. Preoperative chemotherapy may also provide survival benefit. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC remain to be determined.

After surgery, many patients develop regional or distant metastases.[6] Several randomized, controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.[7-13]

Evidence (adjuvant chemotherapy):

Data on individual patient outcomes were collected and pooled into a meta-analysis from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.[9]

With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy.

The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted cautiously as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine.

The meta-analysis as well as the individual studies [7,14] support the administration of postoperative cisplatin-based chemotherapy in combination with vinorelbine.

There were no significant differences in toxic effects, hospitalization, or treatment-related death by age group, although elderly patients received less treatment.[15]

Several other randomized controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.[7-13]

Based on these data, patients with completely resected stage II lung cancer may benefit from postoperative cisplatin-based chemotherapy.[15][Level of evidence: 1iiA]

Radiation therapy

Patients with potentially operable tumors with medical contraindications to surgery or those with inoperable stage II disease and with sufficient pulmonary reserve are candidates for radiation therapy with curative intent.[16] Primary radiation therapy often consists of approximately 60 Gy delivered with megavoltage equipment to the midplane of the volume of the known tumor using conventional fractionation. A boost to the cone down field of the primary tumor is frequently used to enhance local control. Careful treatment planning with precise definition of target volume and avoidance of critical normal structures, to the extent possible, is needed for optimal results; this requires the use of a simulator.

Prognosis:

Among patients with excellent PS, a 3-year survival rate of 20% may be expected if a course of radiation therapy with curative intent can be completed.

Evidence (radiation therapy):

In the largest retrospective series reported to date, 152 patients with medically inoperable NSCLC were treated with definitive radiation therapy. The study reported the following:[17]

This retrospective study also suggested that improved DFS was obtained with radiation therapy doses greater than 60 Gy.[17]

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

Clinical trials of radiation therapy after curative surgery.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Patients with clinical stage IIIA-N2 disease have a 5-year overall survival rate of 10% to 15%; however, patients with bulky mediastinal involvement (i.e., visible on chest radiography) have a 5-year survival rate of 2% to 5%. Depending on clinical circumstances, the principal forms of treatment that are considered for patients with stage IIIA NSCLC are radiation therapy, chemotherapy, surgery, and combinations of these modalities.

Treatment options vary according to the location of the tumor and whether it is resectable.

The preponderance of evidence indicates that postoperative cisplatin combination chemotherapy provides a significant survival advantage to patients with resected NSCLC with occult N2 disease discovered at surgery. The optimal sequence of surgery and chemotherapy and the benefits and risks of postoperative radiation therapy in patients with resectable NSCLC are yet to be determined.

Surgery

If complete resection of tumor and lymph nodes is possible, such patients may benefit from surgery followed by postoperative chemotherapy. Current evidence suggests that lung cancer resection combined with complete ipsilateral mediastinal lymph node dissection (CMLND) is associated with a small-to-modest improvement in survival compared with lung cancer resection combined with systematic sampling of mediastinal nodes in patients with stage I, II, or IIIA NSCLC.[1][Level of evidence: 1iiA]

Evidence (surgery):

The Cochrane Collaboration group reviewed 11 randomized trials with a total of 1,910 patients who underwent surgical interventions for early-stage (I–IIIA) lung cancer.[1] A pooled analysis of three trials reported the following:

Four-year survival was superior in patients with resectable stage I, II, or IIIA NSCLC who underwent resection and CMLND, compared with those who underwent resection and lymph node sampling; the hazard ratio (HR) was estimated to be 0.78 (95% confidence interval [CI], 0.65–0.93; P = .005).[1][Level of evidence: 1iiA]

Conclusions about the efficacy of surgery for patients with local and locoregional NSCLC are limited by the small number of participants studied to date and by the potential methodological weaknesses of the trials.

Neoadjuvant therapy

Neoadjuvant chemotherapy

The role of chemotherapy prior to surgery in patients with stage III-N2 NSCLC has been extensively tested in clinical trials. The proposed benefits of preoperative (neoadjuvant) chemotherapy include the following:

A reduction in tumor size that may facilitate surgical resection.

Early eradication of micrometastases.

Better tolerability.

Evidence (neoadjuvant chemotherapy):

The Cochrane Collaboration group provided a systematic review and meta-analysis of seven randomized controlled trials that included 988 patients and evaluated the addition of preoperative chemotherapy to surgery versus surgery alone.[3] These trials evaluated patients with stages I, II, and IIIA NSCLC.

Preoperative chemotherapy provided an absolute benefit in survival of 6% across all stages of disease, from 14% to 20% at 5 years (HR, 0.82; 95% CI, 0.69–0.97; P = .022).[3][Level of evidence: 1iiA]

This analysis was unable to address questions such as whether particular types of patients may benefit more or less from preoperative chemotherapy.[4]

In the largest trial reported to date, 519 patients were randomly assigned to receive either surgery alone or three cycles of platinum-based chemotherapy followed by surgery.[5] Most patients (61%) had clinical stage I disease, 31% had stage II disease, and 7% had stage III disease.

Postoperative complications were similar between groups, and no impairment of quality of life was observed.

There was no evidence of a benefit in terms of overall survival (OS) (HR, 1.02; 95% CI, 0.80–1.31; P = .86)

Updating the systematic review by addition of the present result suggests a 12% relative survival benefit with the addition of preoperative chemotherapy (1,507 patients, HR, 0.88; 95% CI, 0.76–1.01; P = .07), equivalent to an absolute improvement in survival of 5% at 5 years.[5]

Several randomized, controlled trials and meta-analyses have evaluated the use of postoperative chemotherapy in patients with stage I, II, and IIIA NSCLC.[6-12]

Data on individual patient outcomes were collected and pooled into a meta-analysis from the five largest trials (4,584 patients) that were conducted after 1995 of cisplatin-based chemotherapy in patients with completely resected NSCLC.[6]

With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82–0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy.

The greater effect on survival observed with the doublet of cisplatin plus vinorelbine compared with other regimens should be interpreted with caution as the total dose of cisplatin received was significantly higher in patients treated with vinorelbine.

Three trials have evaluated platinum-based combination chemotherapy followed by surgery versus combined platinum-based combination chemoradiation therapy (60 Gy–69.6 Gy) alone to determine which local treatment modality (surgery or radiation therapy) was most efficacious.[16-18] Although studies were small, enrolling 73, 107, and 333 patients with stage IIIA-N2 disease, respectively, no trial reported a difference in local control or survival.[16-18][Level of evidence: 1iiA]

In the largest series (EORTC-08941), 579 patients with histologic- or cytologic-proven stage IIIA-N2 NSCLC were given three cycles of platinum-based induction chemotherapy.[18] The 333 responding patients were subsequently randomly assigned to surgical resection or radiation therapy. Of the 154 patients (92%) who underwent surgery, 50% had a radical resection, 42% had a pathologic downstaging, and 5% had a pathologic complete response; 4% died after surgery. Postoperative (adjuvant) radiation therapy (PORT) was administered to 62 patients (40%) in the surgery arm. Among the 154 patients (93%) who received radiation therapy, overall compliance to the radiation therapy prescription was 55%, and grade 3-4 acute and late esophageal and pulmonary toxic effects occurred in 4% and 7% of patients; one patient died of radiation pneumonitis.

Rates of progression-free survival were also similar in both groups. In view of its low morbidity and mortality, it was concluded that radiation therapy should be considered the preferred locoregional treatment for these patients.[18]

Adjuvant radiation therapy

The value of PORT has been assessed.[14] Although some studies suggest that PORT can improve local control for node-positive patients whose tumors were resected, it remains controversial whether it can improve survival. The optimal dose of thoracic PORT is not known at this time. The majority of studies cited used doses ranging from 30 Gy to 60 Gy, typically provided in 2 Gy to 2.5 Gy fractions.[14]

As referred to in the National Cancer Institute of Canada and Intergroup Study JBR.10 study (NCT00002583), PORT may be considered in selected patients to reduce the risk of local recurrence, if any of the following are present:[13]

Involvement of multiple nodal stations.

Extracapsular tumor spread.

Close or microscopically positive resection margins.

Evidence (adjuvant radiation therapy):

Evidence from one large meta-analysis, subset analyses of randomized trials, and one large population study suggest that PORT may reduce local recurrence. Results from these studies on the effect of PORT on OS are conflicting.

There is benefit of PORT in stage IIIA-N2 disease, and the role of PORT in early stages of NSCLC should be clarified in ongoing phase III trials. Further analysis is needed to determine whether these outcomes can be modified with technical improvements, better definitions of target volumes, and limitation of cardiac volume in the radiation portals.[8]

Standard Treatment Options for Unresectable Stage IIIA N2 NSCLC

Standard treatment options for patients with unresectable NSCLC include the following:

For treatment of locally advanced unresectable tumor

Radiation therapy with traditional dose and fractionation schedules (1.8–2.0 Gy per fraction per day to 60–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[19]

Although EBRT is frequently prescribed for symptom palliation, there is no consensus about when the fractionation scheme should be used.

For EBRT, different multifraction regimens appear to provide similar symptom relief;[23-28] however, single-fraction radiation therapy may be insufficient for symptom relief compared with hypofractionated or standard regimens, as seen in the NCIC Clinical Trials' Group trial (NCT00003685).[25][Level of evidence: 1iiC]

Evidence of a modest increase in survival in patients with better PS given high-dose EBRT is available.[23,24][Level of evidence: 1iiA]

HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.

Chemoradiation therapy

The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials and meta-analyses. Overall, concurrent treatment may provide the greatest benefit in survival with increase in toxic effects.

Concomitant platinum-based radiation chemotherapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.[29]

Evidence (chemoradiation therapy):

A meta-analysis of patient data from 11 randomized clinical trials showed the following:[30]

Cisplatin-based combinations plus radiation therapy resulted in a 10% reduction in the risk of death compared with radiation therapy alone.[30][Level of evidence: 1iiA]

A meta-analysis of 13 trials (based on 2,214 evaluable patients) showed the following:[31]

A meta-analysis of individual data from 1,764 patients was based on nine trials and showed the following:[29]

The HR of death among patients treated with radiation therapy and chemotherapy compared with radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02), corresponding to an absolute benefit of chemotherapy of 4% at 2 years.

The combination of platinum with etoposide seemed more effective than platinum alone.

Concurrent versus sequential chemoradiation therapy

The results from two randomized trials (including RTOG-9410) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy may provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.[32-35][Level of evidence: 1iiA]

Evidence (concurrent vs. sequential chemoradiation therapy):

In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared with chemotherapy followed by continuous daily radiation therapy to 56 Gy.[32]

Five-year OS favored concurrent therapy (27% vs. 9%).

Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.[32]

In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 60 Gy of radiation therapy, concurrent chemotherapy, or concurrent chemotherapy with cisplatin and vinblastine with twice-daily radiation therapy.[33]

Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[34,36][Level of evidence: 1iiA]

Standard treatment options for superior sulcus tumors include the following:

Radiation therapy alone.

Radiation therapy and surgery.

Concurrent chemotherapy with radiation therapy and surgery.

Surgery alone (for selected patients).

NSCLC of the superior sulcus, frequently termed Pancoast tumors, occurs in less than 5% of patients.[37,38] Superior sulcus tumors usually arise from the apex of the lung and are challenging to treat because of their proximity to structures at the thoracic inlet. At this location, tumors may invade the parietal pleura, chest wall, brachial plexus, subclavian vessels, stellate ganglion, and adjacent vertebral bodies. However, Pancoast tumors are amenable to curative treatment, especially in patients with T3, N0 disease.

Radiation therapy alone

While radiation therapy is an integral part of the treatment of Pancoast tumors, variations in dose, treatment technique, and staging that were used in various published series make it difficult to determine its effectiveness.[37,38]

Prognosis:

Small, retrospective series of radiation therapy in patients who were only clinically staged have reported 5-year survival rates of 0% to 40%, depending on T stage, total radiation dose, and other prognostic factors. Induction radiation therapy and en-bloc resection was shown to be potentially curative.

Evidence (radiation therapy):

In the preoperative setting, a dose of 45 Gy over 5 weeks is generally recommended, while a dose of approximately 61 Gy is required when using definitive radiation therapy as the primary modality.[37,38]

Surgery

Evidence (surgery):

Retrospective case series have reported complete resection was achieved in only 64% of T3, N0 tumors and 39% of T4, N0 tumors.[39]

Chemoradiation therapy

In the first trial (NCT00002642), 110 eligible patients were enrolled with mediastinoscopy negative, clinical T3–4, N0–1 tumors of the superior sulcus.[41] Induction treatment was two cycles of etoposide and cisplatin with 45 Gy of concurrent radiation therapy.

The induction regimen was well tolerated, and only five participants had grade 3 or higher toxic effects.

Pathologic complete response or minimal microscopic disease was seen in 61 (56%) resection specimens. Pathologic complete response led to better survival than when any residual disease was present (P = .02).

Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Disease progression occurred mainly in distant sites.

In the second trial, 75 patients were enrolled and treated with induction therapy with mitomycin C, vindesine, and cisplatin combined with 45 Gy of radiation therapy.[40] Fifty-seven patients (76%) underwent surgical resection, and complete resection was achieved in 51 patients (68%).

There were 12 patients with pathologic complete response.

Major postoperative morbidity, including chylothorax, empyema, pneumonitis, adult respiratory distress syndrome, and bleeding, was observed in eight patients. There were three treatment-related deaths.

The disease-free and OS rates at 3 years were 49% and 61%, respectively; at 5 years, they were 45% and 56%, respectively.[40][Level of evidence: 3iiiDi]

Standard treatment options for tumors that invade the chest wall include the following:

Surgery.

Surgery and radiation therapy.

Radiation therapy alone.

Chemotherapy combined with radiation therapy and/or surgery.

Selected patients with bulky primary tumors that directly invade the chest wall can obtain long-term survival with surgical management provided that their tumor is completely resected. Radical surgery, including chest wall resection, may result in a 5-year survival rate of up to 50%.

Evidence (radical surgery):

In two small case series of 97 and 104 patients, respectively, the 5-year survival rates of patients who had completely resected T3, N0, M0 disease were 44.2% and 67.3%; for T3, N1, M0 disease 5-year rates were 40.0%, and T3; and for N2, M0 disease 5-year rates were 6.2% and 17.9%.[42,43][Level of evidence: 3iiiDi]

In a case series of 309 patients treated at three centers, patients who underwent en bloc resection had superior outcomes compared with patients who underwent extrapleural resections (60.3% vs. 39.1%; P = .03).[44][Level of evidence: 3iiiDi]

Adjuvant chemotherapy is recommended and radiation therapy is reserved for cases with unclear resection margins. Survival rates were lower in patients who underwent incomplete resection and had mediastinal lymph node involvement. Combined modality approaches have been evaluated to improve ability to achieve complete resection.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

Combined modality therapy, including chemotherapy, radiation therapy, and surgery in various combinations.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIA non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Stage IIIB NSCLC Treatment

Based on the Surveillance, Epidemiology, and End Registry, the estimated incidence of stage IIIB NSCLC is 17.6%.[1] The anticipated 5-year survival for the vast majority of patients who present with clinical stage IIIB NSCLC is 3% to 7%.[2] In small case series, selected patients with T4, N0-1 disease, solely as the result of satellite tumor nodule(s) within the primary lobe, have been reported to have 5-year survival rates of 20%.[3,4][Level of evidence: 3iiiA]

For treatment of locally advanced unresectable tumor in patients who are not candidates for chemotherapy.

For patients requiring palliative treatment.

In general, patients with stage IIIB NSCLC do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on the following:

Sites of tumor involvement.

The patient's performance status (PS).

Most patients with excellent PS are candidates for combined modality chemotherapy and radiation therapy with the following exceptions:

Selected patients with T4, N0 disease may be treated with combined modality therapy and surgery similar to patients with superior sulcus tumors.

Sequential or concurrent chemotherapy and radiation therapy

Many randomized studies of patients with unresectable stage III NSCLC show that treatment with preoperative or concurrent cisplatin-based chemotherapy and radiation therapy to the chest is associated with improved survival compared with treatment that uses radiation therapy alone. Although patients with unresectable stage IIIB disease may benefit from radiation therapy, long-term outcomes have generally been poor, often the result of local and systemic relapse. The addition of sequential and concurrent chemotherapy to radiation therapy has been evaluated in prospective randomized trials.

The hazard ratio of death among patients treated with radiation therapy and chemotherapy compared with radiation therapy alone was 0.89 (95% CI, 0.81–0.98; P = .02) corresponding to an absolute benefit of chemotherapy of 4% at 2 years.

The combination of platinum with etoposide seemed more effective than platinum alone. Concomitant platinum-based chemotherapy and radiation therapy may improve survival of patients with locally advanced NSCLC. However, the available data are insufficient to accurately define the size of such a potential treatment benefit and the optimal schedule of chemotherapy.[7]

The results from two randomized trials (including RTOG-9410) and a meta-analysis indicate that concurrent chemotherapy and radiation therapy provide greater survival benefit, albeit with more toxic effects, than sequential chemotherapy and radiation therapy.[8-10][Level of evidence: 1iiA]

In the first trial, the combination of mitomycin C, vindesine, and cisplatin were given concurrently with split-course daily radiation therapy to 56 Gy compared with chemotherapy followed by continuous daily radiation therapy to 56 Gy.[8]

Myelosuppression was greater among patients in the concurrent arm, but treatment-related mortality was less than 1% in both arms.[8]

In the second trial, 610 patients were randomly assigned to sequential chemotherapy with cisplatin and vinblastine followed by 60 Gy of radiation therapy, concurrent chemotherapy, or concurrent chemotherapy with cisplatin and vinblastine with twice-daily radiation therapy.[10]

Two smaller studies also reported OS results that favored concurrent over sequential chemotherapy and radiation, although the results did not reach statistical significance.[10][Level of evidence: 1iiA][11]

Radiation therapy with traditional dose and fractionation schedules (1.8 Gy–2.0 Gy per fraction per day to 60 Gy–70 Gy in 6–7 weeks) results in reproducible long-term survival benefit in 5% to 10% of patients and significant palliation of symptoms.[12]

Evidence (radiation therapy for locally advanced unresectable tumor):

One prospective randomized clinical study showed the following:

Radiation therapy given as three daily fractions improved OS compared with radiation therapy given as one daily fraction.[13][Level of evidence: 1iiA]

Patterns of failure for patients treated with radiation therapy alone included both locoregional and distant failures.

For palliative treatment

Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC, such as the following:

Tracheal, esophageal, or bronchial compression.

Pain.

Vocal cord paralysis.

Hemoptysis.

Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing lesions.[14]

HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.

Although EBRT is frequently prescribed for symptom palliation, there is no consensus about when the fractionation scheme should be used.

Although different multifraction regimens appear to provide similar symptom relief,[16-21] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as shown in the NCIC Clinical Trials' Group trial (NCT00003685).[18][Level of evidence: 1iiC]

Evidence of a modest increase in survival in patients with better PS given high-dose radiation therapy is available.[16,17][Level of evidence: 1iiA]

Patients with stage IIIB disease with poor PS are candidates for chest radiation therapy to palliate pulmonary symptoms (e.g., cough, shortness of breath, hemoptysis, or pain).[12][Level of evidence: 3iiiC] (Refer to the PDQ summaries on Cardiopulmonary Syndromes and Pain for more information.)

Treatment Options Under Clinical Evaluation

Because of the poor overall results, patients with stage IIIB NSCLC are candidates for clinical trials, which may lead to improvement in the control of disease.

Treatment options under clinical evaluation include the following:

New fractionation schedules.

Radiosensitizers.

Combined modality approaches.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIIB non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Randomized controlled trials of patients with stage IV disease and good PS have shown that cisplatin-based chemotherapy improves survival and palliates disease-related symptoms.[5][Level of evidence: 1iiA] Patients with nonsquamous cell histology, good PS, no history of hemoptysis or other bleeding, or recent history of cardiovascular events may benefit from the addition of bevacizumab to paclitaxel and carboplatin. Patients with tumors harboring mutations in EGFR, particularly those from East Asia, never smokers, and those with adenocarcinoma may benefit from EGFR tyrosine kinase inhibitors as an alternative to first- or second-line chemotherapy. Second-line chemotherapy with docetaxel, pemetrexed, or erlotinib also improves survival in patients with good PS.[5][Level of evidence: 1iiA] The role of chemotherapy in patients with poor PS was less certain.

Cytotoxic combination chemotherapy (first line)

The type and number of chemotherapy drugs to be used for the treatment of patients with advanced NSCLC has been extensively evaluated in randomized controlled trials and meta-analyses.

Several randomized trials have evaluated various drugs combined with either cisplatin or carboplatinum in previously untreated patients with advanced NSCLC. Based on meta-analyses of the trials, the following conclusions can be drawn:

Certain three-drug combinations that add so-called targeted agents may result in superior survival.

Platinum combinations with vinorelbine, paclitaxel, docetaxel, gemcitabine, irinotecan, and pemetrexed yield similar improvements in survival. Types and frequencies of toxic effects differ, and these may determine the preferred regimen for an individual patient. Patients with adenocarcinoma may benefit from pemetrexed.

Cisplatin and carboplatinum yield similar improvements in outcome with different toxic effects. Some, but not all, trials and meta-analyses of trials suggest that outcomes with cisplatin may be superior, although with a higher risk of certain toxicities such as nausea and vomiting.

Nonplatinum combinations offer no advantage to platinum-based chemotherapy, and some studies demonstrate inferiority.

Three-drug combinations of the commonly used chemotherapy drugs do not result in superior survival and are more toxic than two-drug combinations.

Evidence (combination chemotherapy):

The Cochrane Collaboration group reviewed data from all randomized controlled trials published between January 1980 and June 2006, comparing a doublet regimen with a single-agent regimen or comparing a triplet regimen with a doublet regimen in patients with advanced NSCLC.[6] Sixty-five trials (13,601 patients) were identified.

In the trials comparing a doublet regimen with a single-agent regimen, a significant increase was observed in tumor response (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.37– 0.47; P < .001) and 1-year survival (OR, 0.80; 95% CI, 0.70–0.91; P < .001) in favor of the doublet regimen. The absolute benefit in 1-year survival was 5%, which corresponds to an increase in 1-year survival from 30% with a single-agent regimen to 35% with a doublet regimen. The rates of grades 3 and 4 toxic effects caused by doublet regimens were statistically increased compared with rates following single-agent therapy, with ORs ranging from 1.2 to 6.2. There was no increase in infection rates in doublet regimens.

The authors concluded that treatment with cisplatin was not associated with a substantial increase in the overall risk of severe toxic effects. This comprehensive individual-patient meta-analysis is consistent with the conclusions of other meta-analyses, which were based on essentially the same clinical trials but which used only published data.

Three literature-based meta-analyses have trials comparing platinum with nonplatinum combinations.[10-12]

The first meta-analysis identified 37 assessable trials that included 7,633 patients.[10]

The toxic effects of platinum-based regimens was significantly higher for hematologic toxic effects, nephrotoxic effects, and nausea and vomiting but not for neurologic toxic effects, febrile neutropenia rate, or toxic death rate. These results are consistent with the second literature-based meta-analysis.

The second meta-analysis identified 17 trials that included 4,920 patients.[11]

Patients treated with a platinum-based regimen benefited from a statistically significant reduction in the risk of death at 1 year (OR, 0.88; 95% CI, 0.78–0.99; P = .044) and a lower risk of being refractory to chemotherapy (OR, 0.87; CI, 0.73–0.99; P = .049).

Among the active combinations, definitive recommendations regarding drug dose and schedule cannot be made, with the exception of pemetrexed for patients with adenocarcinoma.

Evidence (drug and dose schedule):

There has been one meta-analysis of seven trials that included 2,867 patients to assess the benefit of docetaxel versus vinorelbine.[13] Docetaxel was administered with a platinum agent in three trials, with gemcitabine in two trials, or as monotherapy in two trials. Vinca alkaloid (vinorelbine in six trials and vindesine in one trial) was administered with cisplatin in six trials or alone in one trial.

The pooled estimate for overall survival (OS) showed an 11% improvement in favor of docetaxel (HR, 0.89; 95% CI, 0.82–0.96; P = .004). Sensitivity analyses that considered only vinorelbine as a comparator or only the doublet regimens showed similar improvements.

There have been two randomized trials comparing weekly versus every 3 weeks' dosing of paclitaxel and carboplatin, which reported no significant difference in efficacy and better tolerability for weekly administration.[14,15] Although meta-analyses of randomized controlled trials suggest that cisplatin combinations may be superior to carboplatin or nonplatinum combinations, the clinical relevance of the differences in efficacy must be balanced against the anticipated tolerability, logistics of administration, and familiarity of the medical staff for treatment decisions for individual patients.

A large, noninferiority, phase III randomized study compared the OS in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and a PS of 0 to 1.[16] Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles.

This study suggests that cisplatin and pemetrexed are another alternative doublet for first-line chemotherapy for advanced NSCLC and also suggests that there may be differences in outcome depending on histology.

Factors influencing treatment

Histology

Patients with adenocarcinoma may benefit from pemetrexed,[16] EGFR inhibitors, and bevacizumab.

Age versus comorbidity

Evidence supports that elderly patients with good PS and limited comorbidity may benefit from combination chemotherapy. Age alone should not dictate treatment-related decisions in patients with advanced NSCLC. Elderly patients with a good PS enjoy longer survival and a better quality of life when treated with chemotherapy compared with supportive care alone. Caution should be exercised when extrapolating data for elderly patients (aged 70–79 years) to patients aged 80 years or older because only a very small number of patients aged 80 years or older have been enrolled on clinical trials, and the benefit in this group is uncertain.[17,18]

Evidence (age vs. comorbidity):

Platinum-containing combination chemotherapy regimens provide clinical benefit when compared with supportive care or single-agent therapy; however, such treatment may be contraindicated in some older patients because of the age-related reduction in the functional reserve of many organs and/or comorbid conditions. Approximately two-thirds of patients with NSCLC are aged 65 years or older and approximately 40% are aged 70 years or older.[19] Surveillance, Epidemiology, and End Results (SEER) data suggest that the percentage of patients aged older than 70 years is closer to 50%.

A review of the SEER Medicare data from 1994 to 1999 found a much lower rate of chemotherapy use than expected for the overall population.[20] It also suggested that elderly patients may have more comorbidities or a higher rate of functional compromise that would make study participation difficult, if not contraindicated, and lack of clinical trial data may influence decisions to treat individual patients with standard chemotherapy.

Single-agent chemotherapy and combination chemotherapy clearly benefit at least some elderly patients. In the Elderly Lung Cancer Vinorelbine Italian Study, 154 patients who were older than 70 years were randomly assigned to vinorelbine or supportive care.[21]

Patients who were treated with vinorelbine had a 1-year survival rate of 32%, compared with 14% for those who were treated with supportive care alone. Quality-of-life parameters were also significantly improved in the chemotherapy arm, and toxic effects were acceptable.

A more recent trial from Japan compared single-agent docetaxel with vinorelbine in 180 elderly patients with good PS.[22]

Retrospective data analyzing and comparing younger (age <70 years) patients with older (age ≥70 years) patients who participated in large, randomized trials of doublet combinations have also shown that elderly patients may derive the same survival benefit, although with a higher risk of toxic effects in the bone marrow.[17,18,23-26]

Performance status (PS)

PS is among the most important prognostic factors for survival of patients with NSCLC.[27] The benefit of therapy for this group of patients has been evaluated through retrospective analyses as well as through prospective clinical trials.

The results support further evaluation of chemotherapeutic approaches for both metastatic and locally advanced NSCLC; however, the efficacy of current platinum-based chemotherapy combinations is such that no specific regimen can be regarded as standard therapy. Outside of a clinical trial setting, chemotherapy should be given only to patients with good PS and evaluable tumor lesions, who desire such treatment after being fully informed of its anticipated risks and limited benefits.

Evidence (performance status):

The Cancer and Leukemia Group B trial (CLB-9730), which compared carboplatin and paclitaxel with single-agent paclitaxel, enrolled 99 patients with a PS of 2 (18% of the study's population).[25]

When compared with patients with a PS of 0 to 1, who had a median survival of 8.8 months and a 1-year survival of 38%, the corresponding figures for patients with a performance status of 2 were 3.0 months and 14%, respectively; this demonstrates the poor prognosis conferred by a lower PS. These differences were statistically significant.

When patients with a PS of 2 were analyzed by treatment arm, those who received combination chemotherapy had a significantly higher response rate (24% vs. 10%), longer median survival (4.7 mo vs. 2.4 mo), and superior 1-year survival (18% vs. 10%), compared with those who were treated with single-agent paclitaxel.[25]

A subset analysis of 68 patients with a PS of 2 from a trial that randomly assigned more than 1,200 patients to four platinum-based regimens has been published.

Despite a high incidence of adverse events, including five deaths, the final analysis showed that the overall toxic effects experienced by patients with a PS of 2 was not significantly different from that experienced by patients with a PS of 0 to 1.

An efficacy analysis demonstrated an overall response rate of 14%, median survival time of 4.1 months, and a 1-year survival rate of 19%; all were substantially inferior to the patients with PS of 0 to 1.

A phase II randomized trial (E-1599) of attenuated dosages of cisplatin plus gemcitabine and carboplatin plus paclitaxel included 102 patients with a PS of 2.[28]

Response rates were 25% and 16%, median survival times were 6.8 months and 6.1 months, and 1-year survival rates were 25% and 19%, respectively. None of these differences was statistically significant, but the survival figures were longer than expected on the basis of historical controls.

Results from two trials suggest that patients with a PS of 2 may experience symptom improvement.[29,30]

In a randomized study of 878 patients with recurrent or advanced stage IIIB or stage IV NSCLC, 444 patients received paclitaxel and carboplatin alone, and 434 patients received paclitaxel and carboplatin plus bevacizumab.[31] Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or PS (ECOG PS >1) were excluded.

The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (HR for death, 0.79; P = .003).

Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P < .001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including five from pulmonary hemorrhage.

For this subgroup of patients with NSCLC, the addition of bevacizumab to paclitaxel and carboplatin may provide survival benefit.[31][Level of evidence: 1iiA]

Another randomized phase III trial investigated the efficacy and safety of cisplatin/gemcitabine plus bevacizumab.[32] Patients were randomly assigned to receive cisplatin (80 mg/m2) and gemcitabine (1,250 mg/m2) for up to six cycles, plus low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo every 3 weeks until disease progression. The primary endpoint was amended from OS to PFS during the course of the study. A total of 1,043 patients were accrued (placebo group, n = 347; low-dose group, n = 345; high-dose group, n = 351).

Objective response rates were also improved with the addition of bevacizumab, and they were 20.1%, 34.1%, and 30.4% for placebo, low-dose bevacizumab, and high-dose bevacizumab plus cisplatin/gemcitabine, respectively.

Incidence of grade 3 or greater adverse events was similar across arms.

Grade 3 or greater pulmonary hemorrhage rates were 1.5% or less for all arms, despite 9% of patients receiving therapeutic anticoagulation.

These results support the addition of bevacizumab to platinum-containing chemotherapy, but the results are far less impressive than when the carboplatin-paclitaxel combination was used.

Furthermore, no significant difference in survival was shown in this study, as reported in abstract form.

Altogether, these findings may suggest that the backbone of chemotherapy may be important when bevacizumab is added.

Two trials have evaluated the addition of cetuximab to first-line combination chemotherapy.[33,34]

In the first trial, 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or stage IV NSCLC, without restrictions by histology or EGFR expression, received cetuximab with taxane (paclitaxel or docetaxel with carboplatin) or combination chemotherapy.[33]

The addition of cetuximab did not result in a statistically significant improvement in PFS, the primary study endpoint, or OS.

A survival benefit was seen in all histological subgroups; however, survival benefit was not seen in non-white or Asian patients. Only the interaction between the treatment and the ethnic origin was significant (P = .011).

It is not clear whether the differences in outcome in these two studies are the result of differences in the study populations, tumor characterization for EGFR expression, or chemotherapy regimens.

EGFR tyrosine kinase inhibitors (first line)

Selective patients may benefit from single-agent EGFR tyrosine kinase inhibitors. Randomized controlled trials of patients with chemotherapy-naïve NSCLC and EGFR mutations have shown that EGFR inhibitors improved PFS but not OS and have favorable toxicity profiles compared with combination chemotherapy.

Evidence (EGFR tyrosine kinase inhibitors):

A phase III, multicenter, randomized trial compared gefitinib with carboplatin plus paclitaxel as first-line treatment in clinically selected patients in East Asia who had advanced adenocarcinoma of the lung and had never smoked or were former light smokers.[36]

The study met its primary objective of demonstrating the superiority of gefitinib as compared with the carboplatin-paclitaxel combination for PFS (HR for progression or death, 0.74; 95% CI, 0.65–0.85; P < .001).

The median PFS was 5.7 months in the gefitinib group and 5.8 months in the carboplatin-paclitaxel group.[36][Level of evidence: 1iDiii]

Following the time that chemotherapy was discontinued and while gefitinib was continued, the PFS curves clearly separated and favored gefitinib.

The 12-month PFS rates were 24.9% with the gefitinib group and 6.7% with the carboplatin-paclitaxel group.

More than 90% of the patients in the trial with mutations had either del19 or exon 21 L858R mutations, which have been shown to be sensitive to EGFR inhibitors. In the subgroup of patients with a mutation, PFS was significantly longer among those who received gefitinib (HR, 0.48; 95% CI, 0.36–0.64; P < .001), whereas, in the subgroup of patients who were negative for a mutation, PFS was significantly longer in those who received the carboplatin-paclitaxel combination (HR with gefitinib, 2.85; 95% CI, 2.05–3.98; P < .001). There was a significant interaction between treatment and EGFR mutation with respect to PFS (P < .001).[36]

Two phase III trials from Japan prospectively confirmed that patients with NSCLC and EGFR mutations have improved PFS but not OS when treated with gefitinib.[37,38]

In the first trial, 230 chemotherapy-naïve patients with metastatic, NSCLC, and EGFR mutations were randomly assigned to receive gefitinib or carboplatin-paclitaxel.[37]

In the planned interim analysis of data for the first 200 patients, PFS was significantly longer in the gefitinib group than in the standard-chemotherapy group (hazard ratio for death or disease progression with gefitinib, 0.36; P < .001), resulting in early termination of the study.

The gefitinib group had a significantly longer median PFS (10.8 months vs. 5.4 months in the chemotherapy group; HR, 0.30; 95% CI, 0.22–0.41; P < .001).[37][Level of evidence: 1iiDiii] The median OS was 30.5 months in the gefitinib group and 23.6 months in the chemotherapy group (P = .31).

In the second trial, the West Japanese Oncology Group conducted a phase 3 study (WJTOG3405) in 177 chemotherapy-naïve patients aged 75 years or younger and diagnosed with stage IIIB/IV NSCLC or postoperative recurrence harboring EGFR mutations (either the exon 19 deletion or L858R point mutation).[38]

Patients were randomly assigned to receive either gefitinib or cisplatin plus docetaxel (administered every 21 days for three to six cycles). The primary endpoint was PFS.

In an open-label, randomized, phase III trial (NCT00874419) from China, 165 patients older than 18 years with histologically confirmed stage IIIB or IV NSCLC and a confirmed activating mutation of EGFR (exon 19 deletion or exon 21 L858R point mutation) received either oral erlotinib (150 mg/day) until they experienced disease progression or unacceptable toxic effects, or up to four cycles of gemcitabine plus carboplatin.[39]

The above trials demonstrated that EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib are superior to the platinum combination chemotherapy as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. It is likely that these results are applicable to non-Asian populations.

In a European study (EURTAC), 1,227 patients with advanced NSCLC were screened for EGFR mutations. Of these, 174 patients with EGFR mutations were randomly assigned to receive erlotinib or platinum-based chemotherapy.[40] The primary endpoint was PFS.

In an interim analysis of the first 153 patients, PFS in the chemotherapy arm was 5.2 months (95% CI, 4.5–5.8) compared to 9.7 months (95% CI, 8.4–12.3) in the erlotinib arm (HR, 0.37; P < .0001). Median survival was 19.3 months in the chemotherapy arm and 19.5 months in the erlotinib arm (HR, 0.80; P = .42).[41][Level of evidence: 1iiDiii]

Maintenance therapy following first-line chemotherapy

One treatment strategy that has been investigated extensively in NSCLC is maintenance therapy following initial response to chemotherapy. Options for maintenance therapy that have been investigated include the following:

Continuing the initial combination chemotherapy regimen.

Continuing only single-agent chemotherapy.

Introducing a new agent as "maintenance."

Multiple randomized trials have evaluated the efficacy of continuing first-line combination cytotoxic chemotherapy beyond three to four cycles.

Evidence (maintenance therapy following first-line chemotherapy):

None of the trials of continued cytotoxic combinations showed a significant OS advantage with additional or longer durations beyond four cycles.

Three trials found statistically significantly improved PFS or time to progression with additional chemotherapy.[42-44]

These data suggest that PFS, but not OS, may be improved either by continuing an effective chemotherapy beyond four cycles or by immediate initiation of alternative chemotherapy. The improvement in PFS, however, is tempered by an increase in adverse events from additional cytotoxic chemotherapy and no consistent improvement in quality of life. For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of cytotoxic chemotherapy until disease progression or the initiation of a different chemotherapy prior to disease progression. Collectively, these trials suggest that first-line cytotoxic combination chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is not responding to treatment; it can be administered for no more than six cycles.[42,43,45,46]

The findings of two randomized trials (NCT00102804 and NCT00789373) have shown outcomes with the addition of pemetrexed following standard first-line platinum-based combination chemotherapy.[44,47]

In the first trial, 663 patients with stage IIIB or stage IV disease who had not progressed on four cycles of nonpemetrexed platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed or placebo until disease progression.[47]

Higher than grade 3 toxicity and treatment discontinuations resulting from drug-related toxic effects were higher in the pemetrexed group than in the placebo group.

No pemetrexed-related deaths occurred.

Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs. 149 [67%]; P = .0001).

Quality of life during maintenance therapy with pemetrexed was similar to placebo, except for a small increase in loss of appetite and significantly delayed worsening of pain and hemoptysis as assessed using the Lung Cancer Symptom Scale.[48] The quality-of-life results require cautious evaluation as there was a high degree of censoring (> 50%) for the primary quality-of-life endpoint of time to worsening of symptoms.

Trials have not evaluated maintenance pemetrexed versus pemetrexed at progression.

In the second trial, 539 patients with NSCLC with nonprogression following treatment with pemetrexed and cisplatin were randomly assigned to continued pemetrexed or placebo.[44]

There was a statistically significant improvement in the primary endpoint of PFS (4.1 months vs. 2.8 months (HR, 0.62; 95% CI, 0.49–0.79) but no improvement in OS.[44][Level of evidence: 1iDiii]

One trial (NCT00556712) reported favorable outcomes with maintenance erlotinib after four cycles of platinum-based doublet chemotherapy in patients with stable disease.[49]

In this trial, 889 patients with NSCLC but without progressive disease were randomly assigned to receive erlotinib (150 mg/day) or placebo until they experienced progressive disease or unacceptable toxicity.[49]

Median PFS was significantly longer with erlotinib than with placebo: 12.3 weeks for patients in the erlotinib group versus 11.1 weeks for those in the placebo group (HR, 0.71; 95% CI, 0.62–0.82; P < .0001).

Radiation therapy

Radiation therapy may be effective in palliating symptomatic patients with local involvement of NSCLC with any of the following:

Tracheal, esophageal, or bronchial compression.

Pain.

Vocal cord paralysis.

Hemoptysis.

Superior vena cava syndrome.

In some cases, endobronchial laser therapy and/or brachytherapy have been used to alleviate proximal obstructing lesions.[1]

Although EBRT is frequently prescribed for symptom palliation, there is no consensus on which fractionation scheme should be used. Although different multifraction regimens appear to provide similar symptom relief,[52-57] single-fraction radiation may be insufficient for symptom relief compared with hypofractionated or standard regimens, as evidenced in the NCT00003685 trial.[2][Level of evidence: 1iiC] Evidence of a modest increase in survival in patients with a better PS given high-dose radiation therapy is available.[4,58][Level of evidence: 1iiA] In closely observed asymptomatic patients, treatment may often be appropriately deferred until symptoms or signs of a progressive tumor develop.

Evidence (radiation therapy):

A systematic review identified six randomized trials of high-dose rate brachytherapy (HDREB) alone or with EBRT or laser therapy.[59]

HDREB provided palliation of symptomatic patients with recurrent endobronchial obstruction previously treated by EBRT, when it was technically feasible.

Treatment Options Under Clinical Evaluation

Treatment options under clinical evaluation include the following:

New chemotherapy regimens.

Other systemic agents.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IV non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.

The use of chemotherapy has produced objective responses and small improvement in survival for patients with metastatic disease.[12][Level of evidence: 1iiA] In studies that have examined symptomatic response, improvement in subjective symptoms has been reported to occur more frequently than objective response.[13,14] Informed patients with good performance status (PS) and symptomatic recurrence can be offered treatment with a platinum-based chemotherapy regimen for palliation of symptoms. For patients who have relapsed after platinum-based chemotherapy, second-line therapy can be considered.

Evidence (chemotherapy and targeted therapy):

Two prospective, randomized studies have shown an improvement in survival with the use of docetaxel compared with vinorelbine, ifosfamide, or best supportive care;[2,15] however, criteria for the selection of appropriate patients for second-line treatment are not well defined.[16]

A meta-analysis of five trials of 865 patients assessing the efficacy and safety of docetaxel administered weekly or every 3 weeks has been reported.[17] In that analysis the following was shown:

A randomized, phase III trial of 571 patients designed to demonstrate the noninferiority of pemetrexed compared with docetaxel showed no difference in response rates, progression-free survival (PFS), or overall survival (OS).[3][Level of evidence: 1iiA] Of note, patients with squamous histology benefited from docetaxel and those with nonsquamous histologies appeared to benefit more from pemetrexed.[18]

Two randomized, placebo-controlled trials indicated that erlotinib prolongs survival and time to deterioration in symptoms in patients with NSCLC after first-line or second-line chemotherapy compared to placebo [19,20] but does not improve survival compared to standard second-line chemotherapy with docetaxel or pemetrexed.[21]

The trial of erlotinib versus best supportive care included 731 patients; 49% had received two prior chemotherapy regimens and 93% had received platinum-based chemotherapy.

OS was 6.7 months among those who had received two prior chemotherapy regimens and 4.7 months among those who had received platinum-based chemotherapy. The HR was 0.70 (P < .001) in favor of erlotinib.[19][Level of evidence: 1iiA]

In the trial (NCT00556322), which was designed to show the superiority of erlotinib versus standard second-line chemotherapy following progression on first-line platinum combination therapy, 424 patients were randomly assigned.

In a large, randomized trial, gefitinib was compared with docetaxel in patients with locally advanced or metastatic NSCLC who had been pretreated with platinum-based chemotherapy.[5] The primary objective was to compare OS between the groups with coprimary analyses to assess noninferiority in the overall population and superiority in patients with high epidermal growth factor receptor (EGFR) gene copy number in the intention-to-treat population. The 1,466 patients were randomly assigned to receive gefitinib (250 mg per day orally; n = 733) or docetaxel (75 mg/m2 intravenously every 3 weeks; n = 733).

In the gefitinib group, the most common adverse events were rash or acne (49% vs. 10%) and diarrhea (35% vs. 25%). In the docetaxel group, neutropenia (5% vs. 74%), asthenia (25% vs. 47%), and alopecia (3% vs. 36%) were most common.

This trial established noninferior survival of patients treated with gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced NSCLC.

A study (NCT00585195) that screened 1,500 patients with NSCLC for ALK rearrangements identified 82 patients with advanced ALK-positive disease who were enrolled in a clinical trial that was an expanded cohort study instituted after phase I dose escalation had established a recommended dose of crizotinib dual MET and ALK inhibitor of 250 mg twice daily in 28-day cycles.[6] Most of the patients had received previous treatment.

Common toxicities were grade 1 or 2 (mild) gastrointestinal side effects.

Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas.

Objective response rates to erlotinib and gefitinib are higher in patients who have never smoked, in females, in East Asians, and in patients with adenocarcinoma and bronchioloalveolar carcinoma.[23-29] Responses may be associated with sensitizing mutations in the tyrosine kinase domain of the EGFR [24-26,28,29] and with the absence of K-RAS mutations.[27-29][Level of evidence: 3iiiDiii] Survival benefit may be greater in patients with EGFR protein expression by immunohistochemistry or increased EGFR gene copy number by fluorescence in situ hybridization studies,[28,29] although the clinical utility of EGFR testing by immunohistochemistry has been questioned.[30]

Treatment of second primary tumor

A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Whether the new lesion is a new primary cancer or a metastasis may be difficult to determine. Studies have indicated that in most patients the new lesion is a second primary tumor, and after its resection, some patients may achieve long-term survival. Thus, if the first primary tumor has been controlled, the second primary tumor should be resected, if possible.[31,32]

Treatment of brain metastases

Patients who present with a solitary cerebral metastasis after resection of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged DFS with surgical excision of the brain metastasis and postoperative whole-brain radiation therapy (WBRT).[33,34] Unresectable brain metastases in this setting may be treated with radiation surgery.[10]

Because of the small potential for long-term survival, radiation therapy should be delivered by conventional methods in daily doses of 1.8 Gy to 2.0 Gy. Because of the high risk of toxic effects observed with such treatments, higher daily doses over a shorter period of time (i.e., hypofractionated schemes) should be avoided.[35] Most patients who are not suitable for surgical resection should receive conventional WBRT.

Approximately 50% of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of these patients will be suitable for additional treatment.[8] In those selected patients with good PS and without progressive metastases outside of the brain, treatment options include reoperation or stereotactic radiation surgery.[8,10] For most patients, additional radiation therapy can be considered; however, the palliative benefit of this treatment is limited.[36][Level of evidence: 3iiiDiii]

Treatment Options Under Clinical Evaluation

Many patients with recurrent NSCLC are eligible for clinical trials.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent non-small cell lung cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of non-small cell lung cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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